3-haloalkyl benzothiadiazines



United States Patent 3,514,454 3-HALOALKYL BENZOTHIADIAZINES William M. McLamore, Kew Gardens, N.Y., and Gerald D. Laubach, Niantic, Conn., assignors to Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware No Drawing. Original application Aug. 4, 1959, Ser. No. 831,462, now Patent No. 3,440,244, dated Apr. 22, 1969. Divided and this application Dec. 5, 1967, Ser.

Int. Cl. C07d 93/34 US. Cl. 260-243 7 Claims ABSTRACT OF THE DISCLOSURE Novel 3,6-disubstituted-7-sulfamylbenzo-1,1 dioxo lthia-2,4-diazines, their utility as diuretic agents and 5- substitued-2,4-diazines, their utility as diuretic agents and 5-substituted-2,4-disulfamylacylanilide and S-substituted- 2,4-disulfamylaniline intermediates for the same.

This application is a divisional of application Ser. No. 831,462 filed Aug. 4, 1959, and now US. Patent 3,440,244, said latter application being a continuation-in-part of now abandoned application Ser. No. 780,675 filed Dec. 16, 195 8, which in turn is a continuation-in-part of application Ser. No. 715,482 filed Feb. 17, 1958, and now issued as U.S. Patent 3,110,716.

CROSS REFERENCE TO RELATED APPLICATIONS This invention is concerned with a new class of highly elTective therapeutic agents as well as the method of preparing same. In particular, the therapeutic agents of this invention are 3,6-disubstitued-7- sulfamylbenzo-1,1-dioxol-thia-2,4-diazines which have proved to be valuable therapeutic agents. These compounds, hereinafter referred to as 3,6-disubstitued-7-sulfamylbenzothiadiazine dioxides, are represented by the following formula:

wherein A is selected from the group consisting of hydrogen, Cl, F, Br, N0 NH trifluoromethyl, and alkyl and alkoxy each containing from 1 to 3 carbon atoms; Z is an alkylene chain containing from 1 to 3 carbon atoms; Y is selected from the group consisting of S, SO and S0 R is selected from the group consisting of alkyl and alkenyl containing up to 12 carbon atoms and preferably up to 5 carbon atoms; cycloalkyl containing 4 to 6 carbon atoms; napthyl;

wherein k is an integer from 0 to 4 and R is selected from the group consisting of hydrogen, amino, lower alkylamino, nitro, fiuoro, chloro, bromo, lower alkyl and lower alkoxy; W(CH wherein q is an integer from 0 to 3 and W is selected from the group consisting of 3,514,454 Patented May 26, 1970 ice thienyl, thiazolyl, pyrimidyl, pyridyl, furyl, imidazolyl and benzimidazolyl;

wherein m is an integer from 1 to 5;

wherein p is an integer from 0 to 5 and X is selected from the group consisting of NH NER NHNH NHNHR and OR, wherein -R is selected from the group consisting of lower alkyl, phenyl and aralkyl containing 7 to 10 carbon atoms; and

wherein r is an integer from 0 to 5 and R is selected from the group consisting of hydrogen, lower alkyl, phenyl and aralkyl containing 7 to 10 carbon atoms.

The alkylene radicals of which Z is representative are derived from aliphatic groups containing two unoccupied valences which permit them to be further connected as indicated for Z is the structural formula. Such radicals may be straight or branched and contain from 1 to 3 carbon atoms in their principal chain, that is, in the carbon chain between the two unoccupied valences. Preferred compounds are those in which Z contains one carbon atom in the principal chain and up to a total of 3 carbon atoms.

Although in the above formula reference is made to a preferred carbon content of the described alkanoyl, alkylene and hydrocarbon substituents, 3,6-disubstituted-7- sulfamylbenzothiadiazine dioxides containing similar groups with higher carbon content may be employed. For example, the alkylene chain represented by Z may be of higher carbon content than indicated and may also be substituted with various groups, for example, phenyl, aralkyl and alkaryl, which, in turn may be substitued by such groups as halogen, nitro, alkoxy, amino and the like. However, the therapeutic activity of such compounds may tend to decrease. Further, since 3,6-disubstituted-7-sulfamylbenzothiadiazine dioxides containing alkanoyl, alkylene and hydrocarbon substituents ,;,of higher carbon content provide no appreciable advantage and the starting compounds for the production of said compounds are generally less economically advisable, they are not preferred. Oxygen analogs of the present new compounds, that is, compounds in which Y is oxygen, also possess the valuable therapeutic effectiveness herein described.

It is also intended to include within the scope of this invention the base addition salts of the above class of compounds as well as the acid addition salts of those compounds in which R contains a basic nitrogen, such as those in which R contains an amino group or a nitrogen heterocyclic ring. Particularly valuable are salts of acids containing a pharmacologically acceptable anion and bases containing a pharmacologically acceptable cation.

Of particular value because of their high order of activity as diuretic agents are compounds in which substituent A is chloro, methyl or trifluoromethyl.

The valuable new therapeutic agents of this invention may be prepared by a variety of synthetic routes which may be illustrated as follows:

Afl-NH o z SR 112N028 /SO2NH2 4 tetrahydrofuran and the like. The quantity of base employed in the cyclization reaction does not appear to be N A I j-zsn HzNOzS VIII I R s H fit s H I R s H N A NH: (BZCOM; A NHCOZB A ZB HzNOzS somrn HzNOzS -so2NH2 HzNOzS 11 V VI INH kYz COHal A NH: A- NHCOZYR HalOaS S02E31 112N023 SOZNH2 I III RYZ COHaI A- NHGOZYR NH: A W ZYR HalOzS S02H5l HzNOzS or IV The ring closure reaction involving the production of compound IV from compound III, and compound VH1 from compound VII, is brought out by merely contacting the starting compound with a base. Exemplary of suitable bases are inorganic bases such as alkali and alkaline earth metal oxides, carbonates and hydroxides, ammonium hydroxide and their obvious equivalents as well as organic bases such as tertiary amines like pyridine and preferably sterically-hindered tertiary amines, e.g. mono-, diand tri-substituted pyridines such as 2,4,6-collidine, lutidine, 2-chloropyridine, 2,4-dichloropyridine and the like as well as hindered trialkylamines. Preferred tertiary amines are represented by the formula:

in which R; is selected from the group consisting of chloro, bromo and alkyl containing up to 3 carbon atoms, and R and R are each selected from the group consisting of hydrogen, chloro, bromo and alkyl containing up to 3 carbon atoms. The reaction is carried in a reactioninert solvent for best results. Such solvents are readily determined by routine experimentation and include water, lower alkanols, acetone, methyl ethyl ketone, dioxane, dimethylformamide, tetrahydrofuran and the like. The aforementioned liquid tertiary amine may also be used as solvent. By reaction-inert is meant solvents which do not react with the starting compounds under the conditions of the reaction. The inorganic base, preferably the hydroxides, may be used in the form of an aqueous solution generally containing from about 5% to about by weight of hydroxide, although from about 5% to about 15% is preferred since best yields are obtained. Alternatively, solutions of the inorganic base in lower alkanols, e.g. methanol and ethanol, may be used. While the reaction proceeds satisfactorily in aqueous solution, the addition of a reaction-inert organic solvent materiall facilitates production of the desired products by providing a more intimate contact of the reactants which have a somewhat limited solubility in water. Organic solvents useful in this regard are lower alkanols, dimethylformamide and similar lower-alkylated formamides, dioxane,

critical, although it is generally preferred to employ at least an equimolar amount of base and starting compound. Smaller amounts of base may lead to reduced yields. Large excesses of base, say excesses up to 1000% and higher may be utilized. As mentioned above, the amine may be used as solvent for the reaction.

Reaction temperature does not appear to be critical since a wide range of temperature may be used, for example, as low as 0 C. and as high as the reflux temperature of the mixture. The use of high temperature merely shortens the reaction time. It is generally found convenient to carry out this reaction at room temperature followed by a short period of heating at elevated temperature to ensure completeness of reaction. Although product formation is almost instantaneous, for best yields, the reaction is allowed to proceed for from about 1 to about 12 hours, depending on the quantities of reagents used. After the reaction is complete, the product is obtained by standard procedures. For example, solvent and excess amine, if used, may be removed by low pressure distillation and the product freed of residual amine by forming an alkali or alkaline earth metal salt which is water-soluble. The product is then obtained from the metal salt by conventional methods.

Alternatively, the ring closure of the above described starting compounds may be effected by merely heating same. This is best accomplished by heating the acylanilide at its melting temperature. The liquefied acylanilide almost instantly transforms to the desired product as is evidenced by the solidification of the liquefied material within a few minutes of heating. The product is then purified by disolving the aqueous solution of metal carbonate, bicarbonate or hydroxide and precipitating with acid. Of course, this method of cyclization may lead to reduced yield of the desired product due to the formation of byproducts particularly where extreme temperatures are employed, for which reason this method is not preferred.

The ring closure reaction involving the production of compound VI from compound V is brought about in the same way as the procedure for the ring closure of compounds IV and VIII to form the respective compounds III and VII with the exception that inorganic bases, particularly the hydroxides, should not be employed since 5 their use may lead to the production of appreciable amounts of undesired by-products.

The acylation of compound II to produce compound III and compound I to produce compound -]X is brought about by contacting the starting compound with an acyl halide of the formula:

RYZCOHal in which Hal is halogen, (bromo, iodo, fluoro and preferably chloro) and R, Y and Z are as described above. Alternatively, if desired, other equivalent amine acylating agents may be used in lieu of the acyl halide, e.g. the corresponding acid anhydride; mixed anhydride prepared with alkylchlorocarbonates such as methyl and ethyl'chlorocarbonate; lower 'alkyl esters; carbodiimides, such as those of the formula: RYZCON-C-NCOZYR; and even the corresponding acid RYZCOOH.

The reaction is generally effected by merely contacting the selected acyl halide with the starting compound in at least a 1:1 molar ratio. Excess of the acyl halide, up to about 20%, is found to enhance the yield of product. The reaction is preferably carried out in a recation-inert organic solvent, e.g. methyl ethyl ketone, acetone, dioxane, lower alkyl esters of ethylene glycol and diethylene glycol, such as the dimethyl ether of diethylene glycol (diglyme) and of ethylene glycol (monoglyme). A particularly effective solvent is monoglyme, the use of which leads to excellent yields of the desired product. While not essentially, hydrogen halide acceptors may be used in this process. Hydrogen halide acceptors are well known to those skilled in the art, for example, organic amines, such as pyridine, triethylamine, etc., inorganic bases, such as alkali and alkaline earth metal hydroxides and carbonates or their obvious equivalents and the like. Temperature does not appear to be critical in this reaction, a wide range of temperature being found operable, from C. to the reflux temperature of the reactive mixture. The use of high temperature merely shortens the time of the reaction. Generally, time periods of from 1 to about 12 hours, and even longer, may be used depending on the temperature used.

Because of the difi'iculty of preparing suitable acyl halides, RYZCOHal, the compounds in which R contains a functional group including nitrogen are preferably not prepared by this procedure. Compound III structure in which R is:

(CI-I COX, wherein p is an integer from 0 to 5 and X is selected from the group consisting of NII --NHNH NHNHR and HNR wherein R has the meaning defined herein; and

NHRz

(CHzLC-NHR:

wherein r and R have the meaning defined herein; are prepared by reaction of the corresponding mercaptan RSH with a suitable (halo) acylanilide of the structure of compound V. The reaction is carried out in the presence of a substantially equimolar amount of a base, as hereinbefore described. Preferred bases are tertiary amines, as described herein, and alkali (Na, K, Li) or alkaline earth (Ba, Ca, Sr) metal carbonates and bicarbonates since their use leads to excellent yields of desired product. The reaction is advantageously carried out in a reaction-inert organic solvent for the reactants. When the base employed is inorganic, it is usually preferred to use water as reaction solvent to which suitable organic solvents may be added if desired. After reaction is complete, the product is obtained by conventional procedures. Compound IX structure in which R includes a functional group containing nitrogen, as above described in this paragraph, are not prepared by even this procedure due to the interfering sulfonyl halide groups of the aniline compound.

The condensation of a mercaptan (RSH) with compounds V or VI to form compound VIII, and with compound V to form compound VII is carried out in the presence of a base either inorganic or organic, as hereinbefore described. The conversion of compound V to VII is carried out in the presence of one equivalent base, while the other conversions may be effected in the presence of at least an equivalent amount, and usually in the presence of excess base. Large excesses of base have been used without materially reducing the yield of final product. The condensation is usually carried out in a reaction inert solvent, usually water when an inorganic base is employed. A variety of other such solvents may be employed, either alone or in combination with water. While the reactions proceeds satisfactorily in aqueous solution, the addition of an organic solvent materially facilitates production of desired compounds by providing a more intimate contact of the reactants which have a limited solubility in water. Organic solvents suitable for these ends are ketones such as acetone and ethyl methyl ketone, lower alkanols, such as methanol, ethanol and propanols, dimethylformamide and similar loweralkylated formamides, dioxanes, tetrahydrofuran and the like.

Although an equimolar ratio of reactants is found to yield appreciable amounts of product, is is generally preferred to employ excess mercaptan to obtain best yields. Excesses of up to 40 mole-percent are found particularly suitable, while larger excesses, although operable, provide no appreciable advantage.

The reaction is carried out at temperatures of from about 0 C. to about reflux temperature of the reaction mixture, and preferably between 20 and 120 C., for from about 1 to about 12 hours. Heating at higher temperatures and for longer periods of time may lead to reduced yield of the desired product.

After the reaction is complete, the product may be obtained by conventional procedures such as concentration of the reaction mixture. When an inorganic base is employed, the product is obtained by acidification of the resultant metal salt. The product may be recrystallized from appropriate solvents, such as acetone, lower alkanols, acetone-ether mixtures, acetone-alkanol mixtures and the like.

The ammonolysis reaction for the prepartion of compound IV from compound IX (where Hal is halogen) is accomplished by treating the starting compound with aqueous ammonia, which elfects the ammonolysis of the sulfonyl halide groups and ring closure to compound IV. Reaction temperature does not appear to be critical since the reaction takes place over a wide range of temperature, even as low as 0 C. and lower. The use of elevated tempertaure (up to about C.) merely serves to shorten the reaction time. Although an equivalent molar ratio of ammonia may be employed, it is generally preferred to use large excesses of ammonia, particularly if elevated temperature is used, for obvious reasons. Reaction periods of from about 1 to about 8 hours, depending on the temperature, are found to give good yield of product. After the reaction is complete, the product is obtained by acidification of the reaction mixture and filtration. Recrystallization of the product may be carried out as previously described.

The ammonolysis of compound IX to produce compound III is carried out by any of the standard procedures of converting a sulfonyl halide to the corresponding sulfonamide. For example, the his sulfonyl halide starting compound may be treated with gaseous ammonia, liquid ammonia, solutions of ammonia in substantially dry organic solvents, such as butanol, methanol, ethanol, benzene, and the like. The reaction mixture should be substantially free of water to prevent formation of compounds of compound IV. The presence of minor amounts of water does not seriously impede the production of the desired product. It is usually preferred to keep the water concentration below about 2% and preferably below 1% based on the reaction mixture volume.

After the initial vigorous reaction subsides, the reaction mixture may be heated at elevated temperature to ensure completeness of reaction. The product is then obtained by standard procedures as previously described.

The reaction is almost instantaneous on mixing the reactants. Temperature is not critical, although it usually is preferred to use low temperature, say room temperature and even lower to C., since the initial reaction may be quite vigorous.

The ammonolysis of compound I to produce compound II is carried ont by any of the standard procedures of preparing sulfonamides from corresponding sulfonyl halides as described in the previous paragraph. Of course, aqueous ammonia may also be used in this process.

The acylation of compound II to produce compound V may be effected in the usual way, employing an acylating derivative of an acid of the formula:

BZCOOH wherein B and Z are as previously described for example, the acid halide, lower alkyl ester, mixed anhydride with lower alkyl chlorocarbonates, carbodiimides and preferably, the acid anhydride:

(BZCO 0 The reaction is generally effected by heating a mixture of the selected haloacid anhydride with a S-substituted- 2,4-disulfamylaniline at a temperature of from about 60 to about 100 C. Usually a reaction time of from about /2 to about 3 hours is found to give excellent yield of the desired product. Heating for longer periods of time may result in decreased yield. Generally, a 1:1 molar ratio of the reactants may be employed. It is preferred to employ a large excess, for example, from 100 to 300% molar excess, of the selected acid anhydride since shorter reaction times are realized in so doing. Intimate mixing of the reactants while heating is found particularly helpful, although not essential, since an excellent yield of the product is obtained. During the course of the reaction, it is at time found helpful to add a solvent, particularly if the reaction mixture should solidify, thus necessiating prolonged heating which may lead to reduced yield of the product. Liquid halogenated hydrocarbons, for example, chloroform, are found to be particularly suitable solvents. After the reaction is complete, the reaction mixture is treated with water to hydrolyze unreacted anhydrides. The solid residue may be recrystallized from acetone to give the desired 5-substituted-2,4-disulfamyl-(halo)acylanilide.

Additional preparative methods for the preparation of the present new products suggest themselves to one skilled in the art. For example, compound IV products in which Y is S0 or S0 may be prepared from those in which Y is S.

The conversion of the present therapeutic agents in which Y is S to those in which Y is S0 or S0 is effected by reaction with a suitable oxidizing agent. A preferred oxidizing agent is hydrogen peroxide in aqueous solution generally employed at concentrations of from about 30% to 40% by weight although higher or lower percentages of hydrogen peroxide are operable. Alkali metal permanganates may also be employed as oxidizing agents but their use may lead to lower yields of the desired product. The reaction may be conveniently carried out in a solvent such as lower alkanoic acids for example, acetic acid. Other water miscible solvents may be advantageously employed in this oxidation process for example, lower alkanols such as ethanol, methanol, propanol or ketones such as acetone or ethyl methyl ketone. These compounds are prepared employing at least stoichiometric amounts of hydrogen peroxide. Because of its tendency to decompose, it is found advisable to employ excess hydrogen peroxide. Of course, as is known to those skilled in the art, extremely large excesses of the oxidizing agent should be avoided in preparing the present compounds in which Y is S0 to minimize the coproduction of those in which Y is S0 A particularly convenient method of preparation of the former is to react the substrate with about a excess of hydrogen peroxide at room temperature (2030 C.) although lower temperatures may be employed for example, temperatures as low as 0 C. The use of higher temperatures may appreciably reduce the yield of the desired product and hence are preferably avoided. The preparation of those compounds in which Y is S0 may be conveniently carried out by employing a large excess of peroxide, say from 200% to 400% excess and even higher. Heating the reaction mixture is particularly helpful since it materially shortens the reaction time and ensures complete conversion. As is obvious, these latter compounds may also be prepared from those in which Y is SO, which constitute an intermediate stage of oxidation. After the reaction is complete, the product is obtained by conventional procedures for example, concentration and precipitation. Of course, it is obvious that peracids, e.g. peracetic acid, penbenzoic acid, or the like may be used in place of hydrogen peroxide in this process.

The therapeutic agents of this invention in which R is other than (CH COOH or (CHQ COX, as hereindescribed, are effective diuretic agents. In addition to their use as intermediates in the preparation of the final products, compounds VII, VI, V and III in which R is other than (CH COOH or (CH COX as hereindescribed are also effective diuretic agents, especially those represented by compounds VI and VII. These compounds also form base salts as do the hereinbefore described products with both pharmaceutically-acceptable and unacceptable cations which have essentially the same utility as described herein. Those compounds in which R is (CH COX, wherein p is as described above and X is -NH NHR -NHNH or NHNHR are effective hypotensive agents. Of course, hypotensive agents are used for the lowering of blood pressure in humans. The present agents may be used alone or in combination with other therapeutic agents according to standard medical practice. The compounds in which R is (CH COOH or (CHQ COOR are intermediates for the preparation of the present hypotensive agents.

The ideal diuretic agent should principally have an enhancing effect on salt as well as water excretion. Additionally, it should maintain a sustained electrolyte balance of body fluids, for example, maintain normal pH values, normal potassium and bicarbonate levels and effect an equivalent excretion of sodium and chloride ions on a sustained basis. Further, a diuretic agent should have a continued effectivenes during daily administration for protracted periods of time. Many diuretics of the prior art are limited in therapeutic application since they do not possess all of the above described properties. Some cause metabolic acidosis by increasing urinary pH; others cause increased potassium and bicarbonate ion elimination and no increase in chloride elimination. Many diuretics are readily not tolerated in prolonged therapy. Some diuretics initially possess many of these properties but in prolonged application either rapidly lose their desired effects or demonstrate a lack of continuous effective action particularly in salt elimination. Because the use of these diuretics in therapy results in a number of undersirable effects, they have only limited application since they may be used only in seriously restricted conditions. Generally certain diuretics are used in combination with other diuretics so that the combination possesses an appreciable number of the above described properties.

The therapeutic agents of the present invention which have diuretic activity possess a number of the properties of an ideal diuretic which makes them valuable compounds for therapeutic application.

The therapeutic agents of this invention may be administered alone or in combination with pharmaceutically acceptable carriers, the proportion of which is determined by the solubility and chemical nature of the compound, chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets or capsules containing such excipients as starch, milk sugar, certain types of clay and so forth. They may be administered sublingually in the form of troches or lozenges in which the active ingredient is mixed with sugar and corn syrups, flavoring agents and dyes; and then dehydrated sufiiciently to make it suitable for pressing into a solid form. They may be administered orally in the form of solutions which may contain coloring and flavoring agents or they may be injected parenterally, that is intramuscularly, 'intraveneously or subcutaneously. For parenteral administration they may be used in the form of a sterile solution containing other solutes-for example, enough saline or glu cose to make the solution isotonic.

The physician will determine the dosage of the present therapeutic agents which will be most suitable and it will vary with the form of administration and the particular compound chosen, and furthermore, it will vary with the particular patient under treatment. He will generally wish to initiate treatment with small dosages substantially less than the optimum dose of the compound and increase the dosage by small increments until the optimum effect under the circumstances is reached. It will generally be found that when the composition is administered orally, larger quantities of the active agent will be required to produce the same effect as a smaller quantity given parenterally. The compounds are useful in the same manner as other diuretics or hypotensive agents and the dosage level is of the same order of magnitude as is generally employed with these other therapeutic agents. The therapeutic dosage will generally be about 100 to 500 milligrams per day although it may be administered in several different dosage units. Tablets containing from 25 to 250 mg. of active agent are particularly useful.

In the foregoing, reference is made to pharmacologically acceptable anions and cations. Examples of a pharmacologically acceptable anion are iodide, chloride, bro mide, sulfate, methylsulfate, acetate, propionate, tartrate, citrate, gluconate, and so forth. The term, pharmacologically acceptable anion has a definite meaning to one skilled in the art. It is defined as non-toxic anion of any of the simple acids commonly used in pharmacology to neutralize basic medicinal agents when the salt thereof is to be used therapeutically. The pharmacological activity of the molecule is primarily a function of the cation, the anion serving chiefly to supply electrical neutrality. Pharmacologically acceptable cations also have a definite meaning to one skilled in the art. It is defined as a nontoxic cation of basic compounds commonly used in pharmacology to neutralized acid medicinal agents when the salt thereof is to be used therapeutically. The pharmacological activity of the molecule is primarily a function of the anion, the cation serving chiefly to supply electrical neutrality. Commonly employed pharmacologically acceptable cations are, for example, sodium, potassium calcium and magnesium. These acid and base addition salts of the compounds of the present invention may be prepared employing conventional procedures. One such procedure involves treating the subject compounds with an aqueous solution containing an equivalent amount of the reagents, i.e. the harmacologically acceptable base, followed 'by concentration of the resultant mixture to obtain the desired product. Pharmacologically acceptable acids are those which contain the anions described above. Pharmacologically acceptable acids are those which contain the anions described above. Such bases may be, for example, oxides, hydroxides, carbonates or bicarbonates. Of course, salts formed with harmacologically unacceptable acids or bases, while not useful therapeutically, may be used in the purification of the present therapeutic agents and also in the preparation of the harmacologically acceptable salts.

The above described -substituted-2,4-disulfamylaniline and S-substituted aniline bis sulfonyl halides may be prepared by procedures described in the literature, for example, the general procedure described in Monatach. Chem. vol. 48, p. 87 (1927) which involves the treatment of a meta-substituted aniline with from 10 to 20 parts by weight of chlorosulfonic acid followed by the gradual ad dition of from about 90 to 170 parts by weight of sodium chloride. The resultant mixture is heated at approximately C. for about 2 hours after which the reaction mixture is poured into water and the resultant S-substituted aniline-2,4-disulfonyl chloride is filtered and is then treated with concentrated ammonium hydroxide by standard procedures to obtain the corresponding disulfonamide. The meta-substituted anilines, for example, meta-chloro-, meta-fluoro, meta-bromo, meta-nitro, meta-alkanoyl, meta-alkyl, meta-trifluoromethyl and meta-alkoxy anilines, may be readily obtained or prepared by standard procedures known to one skilled in the art. The haloacid anhydride may be prepared by conventional procedures, for example, heating the corresponding haloacid in excess acetic anhydride, followed by removal of the acetic anhydride-acetic oxide mixture so formed leaving the desired haloacid anhydride. The above procedure is commonly employed in the art. Alternatively, the anhydride may be prepared by sublimation in vacuo of the corresponding haloacid. Further, such anhydrides may be prepared by the interaction of the sodium salt of the selected haloacid and the corresponding haloacylhalide, a well known procedure. The herein-described substituted mercaptoacyl halides are prepared by known procedures, e.g. reaction of the corresponding acid with thionyl chloride.

The following examples are given by way of illustration and are not to be construed as limitations of this invention many variations of which are possible without departing from the scope and spirit thereof.

EXAMPLE I 3-benzylthiomethyl-6-chloro-7-su1famyl-1,2,4-benzothiadiazinel, l-dioxide Method A.-A mixture of 7.24 g. (0.02 mole) of 5- chloro-2,4-disulfamyl (a-chloro) acetanilide and 2.98 g. (0.024 mole) benzylmercaptan in 20 ml. of 10% sodium hydroxide to which is added 20 ml. of dimethylformamide is stirred at room temperature for 8 hours. The mixture is then heated for 10 minutes on a steam bath, cooled and acidified with 6 N HCl. The precipitate which forms is filtered and recrystallized from acetone. The product melts at 231-232 C. Elemental analysis gives the following results:

Calculated for C H N O S Cl (percent): C, 41.71; H, 3.3; N, 9.7. Found (percent): C, 41.2; H, 3.3.

Method B.-A mixture of 3-chloromethyl-6-chloro-7- sulfamylbenzothiadiazine-1,1-dioxide (0.02 mole) and benzylmercaptan (0.024 mole) in 20 ml. of 10% sodium hydroxide and 20 ml. of dimethylformamide is stirred at room temperature for 6 hours. After heating for 10 minutes on a steam bath, the mixture is cooled and acidified with 6 N HCl to obtain the product.

Method C.A mixture of 24 g. of 5-chloro-2,4-disulfamyl(S-benzyl)thioglycolanilide in 192 ml. of methanol and 60 ml. of 7% aqueous sodium hydroxide is stirred for 12 hours after which the mixture is heated on a steam bath for one hour. The mixture, after cooling, is poured into 6 N hydrochloric acid and the resulting precipitate filtered, washed with water and dried to obtain the product.

Method D.-Five grams of N-(S-benzylthioglycollyl)- 5-chloroaniline-2,4-bis(sulfonyl chloride) in 50 ml. of concentrated ammonium hydroxide is allowed to stand at room temperature for 12 hours. After stripping excess ammonia, the solution is acidified with 6 N hydrochloric acid to obtain the product which is filtered, washed with water and dried.

1 1 EXAMPLE II 3-benzylsulfinylmethyl-6-chloro-7-sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide The product of Example I (3.5 g.) is dissolved in 25 ml. of acetone and the mixture treated with 2.5 ml. of 30% aqueous hydrogen peroxide in 10 ml. glacial acetic acid. The mixture is stirred for 7 hours and allowed to stand for 8 hours. The crystalline precipitate which forms is filtered, washed with acetone and then water and dried. Recrystallization from methanol-acetone gives a product melting at 225 C. Elemental analysis gives the following results:

Calculated for C H N O S Cl (percent): C, 40.22; H, 3.15; N, 9.38. Found (percent): C, 40.1; H, 3.1; N, 9.1.

This product is also prepared by Methods C and D of Example I from corresponding N-(benzylsulfinylacetyl) aniline derivative.

EXAMPLE HI 3-benzylsulfonylmethyl-6-chloro-7-sulfamyl-1,2,4- benzothiadiazine- 1, l-dioxide 3.5 grams of the product of Example I is dissolved in 25 ml. of acetone and the mixture treated with 5.0 ml. of 30% aqueous hydrogen peroxide in 20 ml. of glacial acetic acid. The resultant mixture is heated on a steam bath for 4 hours after which the product is obtained by concentration. Recrystallization from methanol-acetone gives a product melting at 299300 C. (d.). Elemental analysis gives the following results:

Calculated for C H N O S Cl (percent): C, 38.83; H, 3.04; N, 9.06. Found (percent): C, 38.36; H, 3.03; N, 8.80.

This product is also prepared by Methods C and D of Example I from the corresponding N-(benzylsulfonylacetyl)aniline derivative.

EXAMPLE IV 3-dodecylthiomethyl-6-chloro-7-sulfamyl-1,2,4- benzothiadiazine-l, l-dioxide This compound is prepared using Method A of Example I from dodecylmercaptan and 5-chloro-2,4-disulfamyl (oc-chloro)acetanilide. The product melts at 25 6.5257 C. Elemental analysis agrees with the theoretical values.

EXAMPLE V 3-carboxymethylthiomethyl-6-chloro-7-sulfamy1-1,2,4- benzothidiazine-1,1-dioxide This compound is prepared by Method A of Example I from thioglycollic acid and 5-chloro-2,4-disulfamyl (u-chloro)acetanilide. The product melts at 236-237 C. (d.). Elemental analysis agrees with the theoretical values.

EXAMPLE VI 3-ethylthiomethy1-6-chloro-7 -sulfamy1-1,2,4 benzothiadiazine-1,1-dioxide This compound is prepared by Method A of Example I from ethylmercaptan and 5-chloro-2,4disulfamyl (uchloro) acetanilide. The product melts at 264-265 C. (d.). Elemental analysis agrees with the theoretical values.

EXAMPLE VII 3-carboxyethylthiomethyl-6-chloro-7-sulfamyl-1,2,4- benzothiadiazine-l, l-dioxide This compound is prepared according to Method A of Example I from ,H-mercaptopropionic acid and 5-chloro- 2,4-disulfamyl (a-chloro)acetanilide. The product melts at 218219 C. Elemental analysis agrees with the theoretical values.

1 2 EXAMPLE VIH 3-p-toly1thiomethyl-6-chloro-7-sulfami1y-1,2,4 benzothiadiazine-1,1-dioxide The following compounds are prepared according to the procedures of Example I from corresponding starting compounds:

3-allylthiomethyl-6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide (M.P. 222.5-223 C.)

3-n-butylthiomethyl-6-chloro-7-su1famyl-1,2,4-benzothiadiazine-l,1-dioxide (M.P. 243244 C.)

3-methallylthiomethyl-6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide (M.P. 228230 C.)

3-benzylthiomethyl-6-methyl-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide (M.P. 236-237 C.)

3- 3-thienylthiomethyl) -6-chloro-7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide (M.P. 268269 C.)

3 (p-methoxybenzylthiomethyl) -6-chloro-7- sulfamyl- 1,2,4-benzothiadiazine-1,l-dioxide (M.P. 251- 252.5 C.)

3-(p-fluorobenzylthiomethyl)-6-chloro-7-sulfamyl-1,2,4- benzothiadiazine-l,l-dioxide (M.P. 244-245 C.)

3-[ 1- (benzylthio) ethyl] -6-chloro-7-sulfamyl- 1 ,2,4-benzothiadiazine-1,1-dioxide (M.P. 232.5-2335 C.)

3-furfurylthiomethyl-6-chloro-7-sulfamyl- 1,2,4-benzothiadiazine-1,1-dioxide (M.P. 202-203 C.)

3- (p-hydroxybenzylthiomethyl) -6-chloro-7-sulfamyl- 1,2,4-benzothiadiazine-1,1-dioxide (M.P. 252-253 C.)

3- 3-methoxy-4-hydroxybenzylthiomethyl -6-chloro-7- sulfamyl-1,2,4-benzothiadiazine-1,l-dioxide (M.P. 245-225" C.)

3 6-dimethylaminobenzylthiomethyl) -6-chloro-7- sulfamyl-l,2,4-benzothiadiazine-l, l-dioxide (M. P. 213.52l4 C.)

3 -(2-thenylthiomethyl) -6-chloro-7-sulfamyl-1,2,4-

benzothiadiazine-1,1-dioxide (M.P. 237238 C.)

3 3 -thenylthiomethyl) -6-chloro-7-sulfamyl-1,2,4-

benzothiadiazine-l,l-dioxide (M.P. 213214 C.)

The products of Examples IV-IX are oxidized according to the procedure of Example II to the following sulfoxides:

3-dodecylsulfinylmethyl-6-chloro-7-sulfamyl-1,2,4-

benzothiadiazine- 1 l-dioxide 3-carb oxymethylsulfinylmethyl-6-chloro-7-sulfamyl-1,2,4-

benzothiadiazine- 1, l-dioxide 3 -ethylsulfinylmethyl-6-chloro-7-sulfamyl-1,2,4-

benzothiadiazine-1,1-dioxide 3 -p-tolysulfinyrnethyl-6-chloro-7-sulfamyl-1,2,4-

benzothiadiazine-1,1-dioxide 3 -allylsulfinylmethyl-6-chloro-7- sulfamyl- 1,2,4-

benzothiadiazine- 1, l-dioxide 3-n-butylsulfinylmethyl-6-chloro-7-sulfamyl-1,2,4-

benzothiadiazinel l-dioxide 3-methallylsulfinylmethyl-6-chloro-7-sulfamyl-1,2,4-

benzothiadiazine- 1 l-dioxide 3 -benzylsulfinylmethyl-6-methyl-7-sulfamyl-1,2,4-

benzothiadiazine-l,1-dioxide 3- (3 -thienylsulfinylmethyl) -6-chloro-7-sulfamyl-1,2,4-

benzothiadiazine-1,1-dioxide 3- (p-methoxybenzylsulfinylmethyl) -6-chloro-7-sulfamyl- 1,2,4-benzothiadiazine-1, l-dioxide 3- (p-fiuorobenzylsulfinylmethyl) -6-chloro-7-sulfamyl- 1,2;4-benzothiadiazine-1, l-dioxide 3- 1- (benzylsulfinyl ethyl] -6-chloro-7-sulfamyll ,2,4-

benzothiadiazine- 1, l-dioxide 3 -furfurylsulfinylmethyl-G-chloro-7-sulfamyl-1,2,4-

benzothiadiazine-1,1-dioxide 1 EXAMPLE XII 3- (chloromethyl) -6-chloro-7-sulfamylbenzothiadiazine- 1,1-dioxide A mixture of 3.6 grams (0.01 mole) of 5-chloro-2,4- disulfamyl (u-chloro)acetanilide and 2.42 grams (0.02 mole) of 2,4,6-collidine is added to cc. of dimethylformamide and the mixture allowed to stand at room tem perature until homogeneous. After heating for 1 hour on a steam bath, the mixture is evaporated under reduced pressure to a gummy residue which on trituration with dilute hydrochloric acid solidifies. The solid material, 2.2 grams, after filtration and drying, melts at 284-290 C. (d.). Thematerial is purified by dissolving in 25 ml. of 2% sodium bicarbonate, filtering through charcoal and reprecipitating with dilute hydrochloric acid. The recrystallized material melts at 328330 C.

The procedure of this example is repreated employing the following sterically-hindered tertiary amines; 2,4-lutidine, 2,6 lutidine, 2,4 dichloropyridine, 2 methyl-4- ethyl-pyridine 2-i-propyland 2-n-propylpyn'dine. Comparable results are obtained.

EXAMPLE XIII 3-grams of 5 chloro-2,4-disulfamyl (a-chloro)acetanilide are heated to the melting temperature (approximately 236 C.) and in approximately 5 minutes the liquified starting compound solidifies to a light tan solid, 2.7 grams being obtained. The product, 3-(chloromethyl)-6-chloro- 7-sulfamylbenzothiadiazine-1,l-dioxide is recrystallized by precipitation, from sodium carbonate solution with dilute hydrochloric acid.

EXAMPLE XIV S-(B-chloroethyl)-6-ch10ro-7-sulfamylbenzothiadiazine- 1,1-dioxide An equimolar mixture of 5 chloro-2,4-disulfamyl(pchloro)propionanilide and 2-bromopyridine in dimethylformamide is allowed to stand at room temperature until homogeneous. After heating for 1 hour on a steam bath, the mixture is evaporated under reduced pressure to a gummy residue which on trituration with dilute hydrochloric acid solidifies. The solid material after filtration and drying is purified by dissolving in aqueous potassium carbonate, filtered through charcoal and reprecipitated TABLE II A B Z Br Br CH2 F C1 (CH2)! CF: F CH2 0 H3 B1 (0 Hz)3 CH3 C1 CH2 103E! C1 (0112):) OCaH7 Cl (CH3): NO: Cl CH2 Cl F (CH2): CF I (C H2): H Cl CH2 H Br CH2 CH B1 CH2 H Cl (C H2): C1 C1 CH(C H CH Cl CH(CH CF3 Cl CH(CH3)CH3 B R Cl CH(CH The compounds of Table II are converted to various 3,6 di-substituted-7-sulfamyl-1,2,4-benzothiadiazine-1,1- dioxides of this invention by the procedure of Method B, in Example I.

EXAMPLE XVI A mixture of 2 g. (0.007 mole) of 5-chloro-2,4-disulfamylaniline and 5.0 g. (0.029 mole) of 04 chloroacetic anhydride is heated with stirring at 100 C. for two hours. The solid reaction mixture is then triturated in 50 ml. of water after which the mixture is filtered, washed with water and dried to obtain 2.1 g. of 5-chloro-2,4-disulfamyl (uchloro)acetanilide. The product is crystallized from acetone-ether to obtain a pure sample, M.P. 235.5-236 C. Elemental analysis gives the following results:

Calculated for C H O N Cl S (percent): C, 26.53; H, 2.50; N, 11.60. Found (percent): C, 26.41; H, 2.51; N, 11.90.

EXAMPLE XVII A mixture of 9.3 g. (0.035 mole) of 5-methyl-2,4-disulfamyl aniline and 25 g. (0.15 mole) of tat-chloroacetic anhydride is heated at 60 C. After 15 minutes the mixture solidified. Fifty milliliters of chloroform are then added and heating is continued for a total of 3 hours. The mixture is then cooled, filtered and washed with chloroform. The solid residue is then triturated with 50 ml. of

with (mute hydrochloric ac1d water, filtered and recrystallized from acetone after treat ment of the hot acetone solution with activated carbon. EXAMPLE XV Eight grams of 5-methyl-2,4-disulfam l a-ChlOl'O acetao Y a The following 3-(haloalkyl)-6-subst1tuted benzothlamhden 222 223 i' Elemimal diazine-l,l-dioxides are prepared according to the proceanalysls of the Product agreed wlth the calcu ated Va dure described in Exam les XIII and XIV.

P EXAMPLE xvm A 213 A member of 5-subst1tuted-2,4-d1sulfamyl (halo)acy1- NH anilides are prepared according to the procedure of Exam- HzNOZs S/ ples XVI and XVII. The experimental data is summarized in the following table in which is given the products and reactants used.

TABLE III 5-substituent of Reaction 5-substituted-2.4- Molar Temp Time 5-substituted-2,4-disulfamyl (halo)acylanilide disull'amyl aniline .Anhydrides Ratio 0.) (hrs.)

5-fluoro-2,4-disulfamil a-chlOIO) propioanilide Fluoro a-Chloroacetic 4:1 100 pg 5-n-pr0pyl-2,4-d isuliamyl (fl-bromo) pro 'onailide. n-Propopy fl-Bromopropionl 2:1 100 1 5-propoxy-2,4-d1sulfamyl (a-chlqro) acetamhde Propo y B-Chloroacetic- 3:1 3 2,4-disulfamyl (a-chloro) acetanllide Hydrogen .d0 2:1 1 5-Gl1l010-Z,4-dlSl1lfamY1 (7-0111010) butyranilide Chloro 'y-Chlorobutytic 1:1 100 1 5-tr1fluor0methyl-2,4-disu1famyl (a-chloro) propionanil1de Trifluoromethyl a-Chloropropionic 2:1 100 1 5-1-propyl-2,4-disu1famyl (u-chloro) acetamlide -Propyl a-Ohloroacetic-.- 4:1 100 5-chloro-2,4-di sulfamyl (fi-bromo) propion anilide Chloro B-Bromoyropiono 3:1 60 3 5-b rom0-2,4-d1sulfamyl (v-bromo) acetanilide Bromo. a-Bromoacetic.-- 4:1 60 2 5-n1tro-2,4-disulfamyl ('y-bromo) butyranilide..- Nitro 'y-Bromolrutytlc 0:1 100 1 5-methyl-2,4disuliamyl (6-chl0r0) propionanilide Methyl 6Chlor0propionic 2:1 100 2 5-ethyoxy-2,4-d1sulfamyl (fl-bromo)propionamlide Ethoxy fi-Bromopropionic 3:1 100 1 2,4-d1sulfan1y l(B-bromo) propionanilide. Hydrogen o 3:1 00 1 5-chloro-2,4-d1su 1famyl ('y-ch1oro)butyranil1de hlor0 l3 chloroyroyiomc 1:2 100 2 5-methoxy-2,4 -d1sulfamyl (B-ehloro) propionanilid Methoxy B-Chloroyropionic 3:1 60 3 5-br0mo-2,4-d1sulfamyl r-chloro) butyl am11de romo. 0-Ch1orokutytic 0:1 100 1 5-methyl-2,4-dis1 1lfamyl (a-bromo) acetanilide Methoxy a-Bromoaoetie 4:1 100 M 5-methoxy-2,4 -d1sulfamyl (a-iodo) acetanilide Methoxy a-Iodoacetic 3:1 60 3 5-bromo-2,4,dxsulfamyl (a-chloro) acetanilide Bromo a-chloroacetlc 4:1 100 19 The following compounds are prepared by reaction of the corresponding lower alkyl ester with concentrated ammonia, hydrazine, an amine or a substituted hydrazine.

H- (S-benzylthioglycollyl -chloroaniline-2,4-

disulfonyl chloride EXAMPLE XXI The hydrochloride of 3-p-aminophenylthiomethyl-6- chloro 7 sulfamyl-l,2,4-benzothiadiazine-1,1-dioxide is prepared by dissolving this compound in an aqueous solution containing an equivalent molar amount of hydrochloric acid. The solution is then concentrated under reduced pressure to obtain the corersponding hydrochloride. This procedure is employed in the preparation of other acid salts with hydrobromic acid, hydroiodic acid and sulfuric acid.

The procedure is repeated employing a solution of hydrogen chloride in ethanol with comparable results.

EXAMPLE XXII The hydrochloride of 3-p-aminophenylthiomethyl-6- chloro 7-sulfamyl-1,2,4-benzothiadiazine-1,1-dioxide is dissolved in water to which is then added an equivalent molar amount of silver acetate. The silver chloride precipitate which forms is filtered and the filtrate concentrated under reduced pressure to obtain the acetic acid addition salt.

In a similar maner, the tartaric citric, gluconic and propionic acid addition salts are prepared.

EXAMPLE XXIII The potassium salt of 3-benzylthiomethyl-6-chloro-7- sulfamyl-l,2,4-benzothiadiazine-1,l-dioxide is prepared by dissolving this compound in an aqueous solution containing an equivalent molar amount of potassium carbonate. The resultant solution is concentrated under reduced pressure to obtain the potassium salt.

This procedure is repeated employing aqueous sodium bicarbonate, barium hydroxide and alcoholic sodium hydroxide to obtain the corresponding metal salts. Similarly, metal salts of the other diuretic agents of this invention are prepared.

EXAMPLE XXIV A tablet base is prepared by blending the following ingredients in the proportion by weight indicated:

Sucrose U.S.P. 82.0 Tapioca starch 13.6 Magnesium stearate 4.4

20 Into this base there is blended a sufficient amount of 3- benzylthiomethyl 6 chloro-7-sulfamyl-1,2,4-benzothiadiazine-l,1-dioxide to provide tablets containing mg. of active ingredient.

EXAMPLE XXV Into the tablet base of Example XXIV there is blended a sufiicient amount of 3-benzylsulfonylmethyl-6-chloro-7- sulfamyl-1,2,4-benzothiadiazine-l,l-dioxide to provide tablets containing 50 mg. of active ingredient.

EXAMPLE XXVI Into the tablet base of Example XXIV, there is incorporated a suflicient amount of 3-benzylthiomethyl-6- chloro 7 sulfamyl-1,2,4-benzothiadiazine-l,l-dioxide to provide tablets each containing 25 mg. of active ingredient.

EXAMPLE XXVII 3-carbamylmethylthiomethyl-6-chloro-7-sulfamyl-1,2,4- benzothiadiazine-1,1-dioxide To 3-carboxymethylthiomethyl 6 chloro-7-sulfamyl- 1,2,4-benzothiadiazine-1,l-dioxide (0.02 mole) in 20 ml. of dimethylformamide is added excess phosphorus oxychloride and the mixture stirred until homogeneous. The mixture is heated at 60 C. for one hour after which it is concentrated under reduced pressure. The residue is cooled in an ice bath and treated with concentrated ammonium hydroxide. The excess ammonia is stripped at reduced pressure and the solution acidified with 6 N HCl to obtain the product which is filtered, washed with water, dried and recrystallized from acetone-water.

In similar manner additional amides and hydrazides of Table I are prepared employing R NH R NHNH or NHNH in lieu of ammonia, with corresponding starting compounds.

EXAMPLE XXVIII 3-benzylcarbamylmethylthiomethyl-6-chloro-7-sulfamyl- 1,2,4-benzothiadiazine-l,l-dioxide A mixture of 3-carbethoxymethylthiomethyl-6-chloro- 7-sulfamyl-1,2,4-benzothiadiazine-l,l-dioxide (0.03 mole) in 5 ml. of benzylamine is heated with stirring for 2 hours at C. The cooled solid mass is treated with water which is acidified with 6 N HCl to obtain the product which is recrystallized from acetone-water.

What is claimed is:

1. A compound selected from the group consisting of compounds of the formula:

wherein:

(a) A is selected from the group consisting of hydrogen, Cl, F, Br, N0 trifluoromethyl and alkyl and alkoxy each containing 1 to 3 carbon atoms,

(b) B is halogen,

(e) Z is alkylene containing 1 to 3 carbon atoms and the alkali and alkaline earth metal salts thereof.

2. The compound of claim 1 wherein A is trifluoromethyl and Z contains one carbon atom in the principal chain and up to a total of three carbon atoms.

3. The compound of claim 1 wherein A is methyl, B is bromo and Z contains one carbon atom in the principal chain and up to a total of three carbon atoms.

21 22 4. The compound of claim 1 wherein A is methyl, B is References Cited chloro and Z contains one carbon atom in the principal UNITED STATES PATENTS chain and up to a total of three carbon atoms.

5. The compound of claim 1 wherein A and B are each 3,392,168 7/ 1968 Lund et 260-243 chloro and Z contains one carbon atoms in the principal chain and up to a total of three carbon atoms. 0 NICHOLAS RIZZO Pnmary Exammer 6. The compound of claim 5 wherein Z is methylene. U S Cl X R 7. The compound of claim 1 wherein A and B are each chloro and Z is ethylene. 424246 

